The relationship between weight and pulmonary outcomes in overweight and obese people with cystic fibrosis: A retrospective observational study

Abstract Background A major focus in cystic fibrosis (CF) care aims to increase weight gain. Rates of overweight and obese people with CF have gradually increased over the past decade. Obesity could be a risk for restriction of lung volumes and airway obstruction as well as increase rates of pulmonary exacerbations in people with CF. Aim To assess the relationship between weight categories and pulmonary outcomes in children and adults with CF. Methods Patients 6 years of age and older were categorized into weight categories based on the Centers for Disease Control and Prevention (CDC) definitions. A retrospective chart review was conducted to obtain lung function testing and other outcomes. Results One hundred five patients with a median age of 20.6 years were included in this analysis. 8.4%, 64%, 18%, and 10% of patients were underweight, normal/healthy weight, overweight, and obese, respectively. Forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) (% predicted) did not differ between patients with weights in the normal range versus patients in the overweight/obese categories. Linear regression analysis showed a direct correlation between body mass index (BMI) and FEV1 that continued as BMI entered overweight and obese categories in both pediatric and adult patients. Overweight/obese patients did not have increased rates of pulmonary exacerbations compared to those in the normal/healthy weight category. Conclusion As CF therapies continue to improve, an increasing number of people with CF are exceeding the CDC's normal‐weight range. Gaining weight past the normal range does not appear to negatively impact pulmonary health of people with CF. If this trend of increased weight gain continues, it remains to be seen if it will eventually negatively affect lung health.


| INTRODUCTION
Cystic fibrosis (CF) is a disease characterized by chronic lung inflammation and malabsorption which may lead to failure to thrive in infancy without treatment. 1 CF was first described in 1938 as CF of the pancreas, 2 and before the advent of pancreatic enzyme replacement therapy, infants with CF would often die from malnutrition. 3 Once pancreatic enzyme replacement became available, patients continued to have difficulties gaining weight due to increased metabolic demand from chronic inflammatory lung disease as well as inefficiencies of pancreatic enzyme replacement. 4 Over the years, it has been demonstrated that nutritional status in people with CF, defined as percent predicted weight-for-length or body mass index (BMI), directly correlates with pulmonary function. 5 This has made increased weight gain a major focus within the CF community. The CF Foundation has set a goal for pediatric patients of a BMI in the 50th percentile or greater, with patients defined as being at risk for nutritional failure with a BMI between 10th and 25th percentile, and in nutritional failure with a BMI below the 10th percentile. 6 Recognition of the relationship between BMI and pulmonary function has led to increased efforts to promote weight gain. 7 In 2009, for the first time in the United States, more than half of all people with CF between 2 and 19 years of age had a BMI greater than the 50th percentile. 7 By 2017, this increased to almost 60%. 7 The median BMI percentile has continued to rise in this population, and with it the proportion in overweight and obese categories has also continued to rise. 8 Both otherwise healthy children and children with asthma who are obese have a higher forced vital capacity (FVC) compared to normal-weight peers, with some evidence of airflow obstruction, such as reduced forced expiratory volume in 1 s (FEV 1 )/FVC and increased respiratory system resistance estimated with impulse oscillometry. [9][10][11] In patients with asthma, obesity is associated with disease severity, and in adults, weight reduction has been shown to improve asthma severity and control, pulmonary function, and quality of life. 10,12 The effects of obesity on pulmonary outcomes in people with CF have not been adequately studied. In a study of overweight and obese adults with CF from 2015 to 2017, FEV 1 % predicted was directly related to rising BMI as patients entered the overweight, but not obese, categories. 13 The objectives of this study were to assess the relationship between weight categories and pulmonary outcomes including pulmonary function and rates of pulmonary exacerbations in children and adults with CF.

| METHODS
This is a single-center retrospective observational study. A chart review was performed of patients with CF seen at the Armond V.
Mascia, MD, Cystic Fibrosis Center at New York Medical College from July 1, 2014, to June 30, 2019. Patients were included if they were 6 years of age and older, had a sweat chloride greater than 60 mmol/L or 2 known CF-causing mutations, and were able to meet american thoracic society criteria for adequate spirometry. 14 Patients were excluded if who had undergone any solid organ transplant or were pregnant/lactating. BMI was calculated as weight (kg)/height (m 2 ).
Adults (people over 20 years of age) and children (people 2-20 years of age) were classified based on Centers for Disease Control and Prevention (CDC) criteria for weight distribution based on BMI percentiles or absolute BMI: • Underweight: Children with BMI below 5th percentile, adults with BMI below 18.5.
• Normal or healthy weight: Children with BMI 5th to less than the 85th percentile, adults with BMI 18.5-24.9.
• Overweight: Children with BMI 85th to less than the 95th percentile, adults with BMI 25.0-29.9.
• Obese: Children with BMI equal to or greater than 95th percentile, adults with BMI 30.0 and above.
The presence of cystic fibrosis-related diabetes (CFRD) was determined based on CF Foundation guidelines. 15 Results from spirometry were expressed as % predicted values using global lung initiative norms. 16 Individual FEV 1 % predicted, FVC% predicted, and the absolute ratio of FEV 1 /FVC were calculated as the median of the maximum value of each measure per quarter over the entire study.
Pulmonary exacerbations were defined as the prescription of oral or intravenous antibiotics by the CF clinician for acute respiratory symptoms. Individual annual pulmonary exacerbation rates were calculated by dividing the number of pulmonary exacerbations over the course of the study by the number of years the patient participated in the study.

| Statistical analysis
For the primary analysis, people in each of the CDC weight categories were compared. Patient characteristics including sex, sweat chloride levels, presence of CFRD, treatment with nutritional therapies, treatment with CFTR modulators, and pulmonary outcomes were evaluated for differences among weight categories.

| Pulmonary outcomes
There were no statistically significant differences in annual rates of pulmonary exacerbations between weight categories (Table 1). FEV 1 % predicted FEV 1 /FVC and FEF25-75% predicted were lower in people who were underweight than those in the other weight categories (Table 1, Figure 1). Scattergrams of FEV 1 % predicted and BMI are presented in Figure 2. On linear regression, there was a direct correlation between BMI and FEV 1 % predicted in all weight categories in both children and adults (Figure 2A,B).

| DISCUSSION
It is well established that pulmonary function and nutritional status, as reflected by BMI, are highly correlated in people with CF. 17 However, increasing rates of obesity in people with CF raise the concern that this relationship may not hold true at higher BMIs.  Figure 1). 20 In this singlecenter study, the positive correlation between BMI and pulmonary function continued even in obese patients (see Figures 1-3).
Furthermore, the rates of pulmonary exacerbations were not higher in obese patients (Table 1).
One might speculate that obesity could result in lung restriction, that is, decreased FVC, but this was not noted in this study. In people with CF, the greater the BMI, the greater the FVC. This is consistent with observations in healthy children and children with asthma, though the reasons for this finding are unclear. 11 There was no evidence of restrictive lung disease in those who were obese. Vital capacity was reduced in underweight people with CF when compared to the other weight categories.
While we found people with CF who are obese have higher FEV 1 % predicted than underweight people with CF, we did not find a statistically significant increase in FEV 1 % predicted when obese people with CF were compared to those in the normal or overweight categories. There are multiple potential reasons why people with CF who are obese have higher FEV 1 % predicted than those who are underweight. Pancreatic enzyme use was significantly lower in the obese group. Pancreatic sufficiency and milder lung disease are associated with lower sweat chloride levels, as was seen in the obese group, likely due to relatively increased CFTR function and subsequently less severe disease. 21 Underweight patients in this analysis were more likely to have CFRD. It is well known that CFRD is associated with decline in lung function as well as decreasing nutritional status in people with CF. 22 While this study shows continued improvements in parameters associated with respiratory health in people with CF even as they become obese, there is insufficient evidence to support counseling patients to take steps to increase weight gain beyond the normal/healthy CDC weight category. It is not clear whether worsening rates, and severity, of obesity might eventually begin to have detrimental effects on pulmonary function in people with CF.
We found some evidence of higher rates of ivacaftor use in obese patients compared to the other weight categories, although these differences did not meet statistical significance. It is possible that the continued improvement of airway flows and volumes in obese patients could be attributed to the potentiation of lung CFTR activity by ivacaftor rather than simply the nutritional benefit. We did not find the same trend in those on ivacaftor/lumacaftor or ivacaftor/ tezacaftor. By the end of our study ivacaftor/tezacaftor/elexacaftor has been approved for people with CF who have at least one F508del mutation, and it is possible that almost 90% of people with CF will have highly effective CFTR modulators (HEM) available for treatment. People with CF started on HEM have significant increases in weight and it is concerning that this may contribute to a rapid increase in obesity rates among people with CF. 23 writingreview and editing. Allen J. Dozor: Conceptualization; formal analysis; methodology; project administration; resources; supervision; writingreview and editing.

CONFLICT OF INTEREST
The authors declare no conflict of interest.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request. All authors have read and approved the final version of the manuscript, John Welter has full access to all of the data in this study and take complete responsibility for the integrity of the data and the accuracy of the data analysis.

TRANSPARENCY STATEMENT
The lead author John J. Welter affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

ETHICS STATEMENT
The study was approved by the New York Medical College Institutional Review Board.